RU2141958C1 - Derivatives of 6-methoxy-1h-benzotriazole-5-carboxamide, method of their synthesis and pharmaceutical composition containing thereof - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention describes new derivatives of 6-methoxy- -1H-benzotriazole-5-carboxamide of the formula (I)

where R¹ means ethyl or cyclopropylmethyl; R² means hydrogen atom, methyl or ethyl; n = 1, 2 or 3 and wavy line

Description

 This invention relates to new 6-methoxy-1H-benzotriazole-5-carboxamide derivatives, characterized in that they simultaneously have excellent antiemetic activity and activity enhancing the contractility of the gastrointestinal tract and lower suppressor activity against the central nervous system (CNS) . More specifically, the invention relates to a 6-methoxy-1H-benzothiazole-5-carboxamide derivative in which the nitrogen atom in the amide group (-CONH-) is substituted with a 1-substituted-azacycloalkan-3-yl group with a 7-, 8- or 9 -membered cycle, methods for their preparation, pharmaceutical compositions containing them and new intermediates.

[где R₁ обозначает низший алкил или необязательно замещенный арил(низший)алкил,
R₂ обозначает гидрокси, алкокси, алкенилокси, циклоалкилокси или замещенный алкокси (заместителями являются галоген, гидрокси или оксо),
R₃ обозначает амино, дизамещенный амино или ациламино,
R₄ обозначает галоген или R₃ и R₄ вместе образуют - NH-N=N-,
R₅ обозначает водород или низший алкил,
X обозначает простую связь или низший алкилен,
Y обозначает простую связь или группу, выражаемую формулой:
-CH₂-, -O-, -S-, -SO-, -SO₂ или -NR₆-,
где R₆ обозначает низший алкил или необязательно замещенный арил (низший) алкил; или может образовывать вместе с R₁ этилен,
n равно 0 или 1, и
пунктирная линия обозначает двойную связь, которая может присутствовать, когда Y обозначает -CH₂- и n равно 0, при условии, что:
i) когда Y обозначает -NR₆- или простую связь, n равно 0;
ii) когда Y обозначает -O-, n равно 1;
iii) когда Y обозначает простую связь или -CH₂- и n равно 0, P₁ обозначает необязательно замещенный арил (низший) алкил;
и
iv) когда n равно 0, X обозначает низший алкилен].Prior art
JP-A 104572/1990 discloses that the compounds represented by the following formula [A] have gastrointestinal motility enhancing activity and are useful as antiemetic agents or gastrointestinal motility enhancing agents:

[where R ₁ denotes lower alkyl or optionally substituted aryl (lower) alkyl,
R ₂ is hydroxy, alkoxy, alkenyloxy, cycloalkyloxy or substituted alkoxy (substituents are halogen, hydroxy or oxo),
R ₃ is amino, disubstituted amino or acylamino,
R ₄ is halogen or R ₃ and R ₄ together form —NH — N═N—,
R ₅ is hydrogen or lower alkyl,
X is a single bond or lower alkylene,
Y represents a single bond or group expressed by the formula:
-CH ₂ -, -O-, -S-, -SO-, -SO ₂ or -NR ₆ -,
where R ₆ denotes lower alkyl or optionally substituted aryl (lower) alkyl; or can form together with R ₁ ethylene,
n is 0 or 1, and
the dotted line indicates a double bond that may be present when Y is —CH ₂ - and n is 0, provided that:
i) when Y is —NR ₆ - or a single bond, n is 0;
ii) when Y is —O—, n is 1;
iii) when Y is a single bond or —CH ₂ - and n is 0, P ₁ is an optionally substituted aryl (lower) alkyl;
and
iv) when n is 0, X is lower alkylene].

 However, named JP-A-104572/1990 does not contain a specific description of the compounds of this invention represented by the following formula (I), simultaneously having a 1H-benzotriazole skeleton and a nitrogen containing 7-, 8- or 9-membered aliphatic ring, in particular, their optically active compounds and pharmacological activities of optically active compounds.

(где A-CO обозначает 4-амино-5-хлор-2-метоксибензоил, 5- этилсульфонил-2-метоксибензоил или 2-метокси-4,5- азимидобензоил;
В обозначает аллил или необязательно замещенную бензильную группу и m равно 1 или 2).JP-A-83737/1977 describes that the compounds represented by the following formula [B] are highly active in attenuating the conditioned reflex of avoiding the behavior of the apomorphine-induced stereotypic reaction and methamphetamine-induced stereotypic interaction, and therefore are useful as CNS depressants, in particular, as antipsychotic drugs:

(where A-CO is 4-amino-5-chloro-2-methoxybenzoyl, 5-ethylsulfonyl-2-methoxybenzoyl or 2-methoxy-4,5-azimidobenzoyl;
B is allyl or an optionally substituted benzyl group and m is 1 or 2).

(в которой P¹ обозначает низший алкокси, R² обозначает необязательно замещенный бензил и m равно 1 или 2).In addition, JP-A-100473/1977 describes compounds represented by the following formula [C]:

(in which P ¹ is lower alkoxy, R ² is optionally substituted benzyl and m is 1 or 2).

 However, in the compounds represented by the above formulas [B] or [C], the cycle attached to the amide moiety (-CONH-) is 5- or 6-membered and the nitrogen atom in the cycle is replaced by an allyl or benzyl group and from this point of view they differ from the structure of the compounds represented by the following formula (I) according to this invention. In addition, their pharmacological activity, again, is different from the activity of the compounds of the invention.

On the other hand, it is known that 4-amino-5-chloro-N- [2 (diethylamino) ethyl] -2-methoxybenzamide [common name: metoclopramide; Cf. Merck Index, Ilth ed. 6063 (1989)] has antiemetic activity and, at the same time, activity that enhances the motility of the gastrointestinal tract, and is used by elderly people to treat or prevent functional disorders of the gastrointestinal tract associated with various diseases and the use of therapeutic agents, that enhances the motility (contractility) of the gastrointestinal tract. However, metoclopramide has a CNS-depressant activity resulting from its dopamine, a D ₂ receptor antagonistic activity, which is an obstacle to its clinical use. Due to the increasing complexity of life in human society and the increasing number of elderly people, the number of patients suffering from symptoms associated with gastrointestinal dysfunction is also increasing, and the need for treatment leads to an increase in demand for a compound or compounds with low CNS-depressant activity and at the same time possessing high antiemetic activity and activity that enhances the contraction of the gastrointestinal tract.

Description of the invention
Extensive studies have been carried out and it has been found that 6-methoxy-1H-benzotriazole-5-carboxamide derivatives in which the nitrogen atom in the amide radical (-CONH-) is substituted with the 1-substituted-azacycloalkan-3-yl group is 7-, 8- or The 9-membered ring, in particular, the (R) -6-methoxy-1H-benzotriazole-5-carboxamide derivatives of the R configuration, have both excellent antiemetic activity and activity that enhances the contractions of the gastrointestinal tract and nevertheless have a surprisingly low CNS- depressant activity. Thus, this invention is a complete scientific work.

 The purpose of this invention is to obtain new 6-methoxy-1H-benzotriazole-5-carboxamide derivatives, in particular, (R) -6-methoxy-1H-benzotriazole-5-carboxamide derivatives having an R configuration having simultaneously excellent antiemetic activity and activity that enhances contractions of the gastrointestinal tract. Another objective of the present invention is to develop methods for producing these compounds. A further object of the invention is to provide pharmaceutical compositions containing said compounds. In addition, it is an object of the invention to provide novel intermediates useful in the preparation of compounds of the invention. These and other objectives and advantages of the invention are obvious to those who read this description and follow it.

[где R¹ обозначает этильную или циклопропилметильную группу,
R² обозначает атом водорода, метильную или этильную группу,
n равно 1, 2 или 3, и
волнистая линия

обозначает, что конфигурация заместителей на углеродном атоме, связанном с атомом N в амидном радикале, является рацемической (RS) или оптический активной (R или S)].The invention provides 6-methoxy-1H-benzotriazole-5-carboxamide derivatives represented by the following formula (I), their pharmaceutically acceptable acid addition salts and pharmaceutical compositions containing them:

[where R ¹ denotes an ethyl or cyclopropylmethyl group,
R ² represents a hydrogen atom, a methyl or ethyl group,
n is 1, 2 or 3, and
wavy line

indicates that the configuration of the substituents on the carbon atom bonded to the N atom in the amide radical is racemic (RS) or optically active (R or S)].

(II)
[где R³ обозначает амино-защитную группу и R¹, n и волнистая линия имеют те же значения, что приняты выше для формулы (I)]. Кроме того, изобретение дает промежуточные соединения приведенной ниже формулы (IV) и их соли кислотного присоединения, используемые для получения соединений формулы (I) по данному изобретению:

[где R¹, n и волнистая линия имеют обозначения, принятые для формулы (I)] , в частности, соединения следующей формулы (IVa) и соли их кислотного присоединения, используемые в качестве промежуточных соединений для получения соединений формулы (I), имеющих R - конфигурацию:

[где R¹ и n имеют принятые для формулы (I) значения].The invention also provides compounds represented by the following formula (II) and their acid addition salts used as intermediates for the preparation of compounds of formula (I) in which R ² represents a hydrogen atom;

(Ii)
[where R ³ denotes an amino protecting group and R ¹ , n and the wavy line have the same meanings as those adopted above for formula (I)]. In addition, the invention provides intermediates of the following formula (IV) and their acid addition salts used to prepare the compounds of formula (I) of this invention:

[where R ¹ , n and the wavy line are used for the formula (I)], in particular, compounds of the following formula (IVa) and salts of their acid addition, used as intermediates for the preparation of compounds of formula (I) having R - configuration:

[where R ¹ and n have the meanings adopted for formula (I)].

 Pharmaceutically acceptable acid addition salts for compounds of formula (I) include, for example, inorganic acid salts that are harmless to the human body, such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc .; and salts of organic acids that are harmless to the human body, such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, etc. The compounds of formula (I) and their acid addition salts can be obtained in the form of a hydrate or solvate, which are also included in the scope of the present invention and the attached items. More specifically, for example, 1/4 hydrate, 1/2 hydrate, monohydrate, 3/2 fumarate • 1/4 hydrate, 3/2 fumarate • 1/2 hydrate, difumarate • 1/2 hydrate, etc. can be named. d.

 Acid addition salts for the intermediates represented by formulas (II) and (IV) or (IVa) include, for example, the same pharmaceutically acceptable salts of the acidic compound as mentioned above. The compounds of formulas (II) and (IV) or (IVa) and their acid addition salts can be obtained in the form of a hydrate or solvate, which are also included in the scope of the present invention and the attached items.

 In the preparation of compounds of formula (I) and their acid addition salts in crystalline form, various types of polymorphism may be present, which are also included in the scope of the invention and the attached items.

[в которых Az обозначает группу формулы [D], приведенной ниже:

(в которой R¹, n и волнистая линия имеют приведенные выше значения)].It will be appreciated that compounds of formula (I) in which R ² is hydrogen are present in the form of tautomers in which the 6-methoxy-1H-benzotriazole radical can be represented by formula (I ′) or (I ″) shown below:

[in which Az denotes a group of the formula [D] below:

(in which R ¹ , n and the wavy line have the above meanings)].

 These tautomers are also included in the scope of the invention and the attached paragraphs.

The structure of the compounds of this invention in which R ² in the formula (I) represents a hydrogen atom is represented by the formula (Ia), and their chemical names are also based on the named structure.

Those compounds in which R ² in the formula (I) represents a methyl or ethyl group do not possess the aforementioned tautomerism.

The term “halogen,” as used herein, means fluoro, chloro, bromo or iodo. Specific examples of “alkyl groups” include methyl, ethyl, propyl and isopropyl. Specific examples of “alkoxy groups” include methoxy, ethoxy, propoxy and isopropoxy. Specific examples of "lower alkanoyl groups" include acetyl and propionyl, and corresponding examples of "lower alkoxycarbonyl groups" include methoxycarbonyl and ethoxycarbonyl. An “optionally substituted benzyl group” is those benzyl groups in which the phenyl moiety is optionally substituted with one or two of the aforementioned halogen atoms, C ₁ -C ₃ alkyl groups and, preferably, C ₁ -C ₃ alkoxy groups, specific examples include 2-, 3- or 4-chlorobenzyl, 3-bromobenzyl, 4-fluorobenzyl, 2,4- or 3,4-dichlorobenzyl, 4-methylbenzyl, 2-, 3- or 4-methoxybenzyl, etc. The term “optionally substituted benzyloxycarbonyl” refers to those benzyloxycarbonyls in which the phenyl radical is optionally substituted with one or two of the aforementioned halogen atoms, C ₁ -C ₃ alkyl groups, C ₁ -C ₃ alkoxy groups, nitro groups, etc. specific examples include benzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl and 4-methoxybenzyloxycarbonyl. The term “amino protecting groups” means those protecting groups that can be removed by hydrolysis or hydrogenolysis, examples thereof include the previously defined groups: lower alkanoyl, trifluoroacetyl, lower alkoxycarbonyl, optionally substituted benzyl and optionally substituted benzyloxycarbonyl, benzyl and acetyl are particularly preferred.

As preferred examples of the compounds of this invention represented by formula (I), the following compounds and their pharmaceutically acceptable salts of acid addition may be given:
N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide,
(R) - N- (1-ethyl-1H-hexahydroazepin-3-yl) -b-methoxy-1H-benzotriazole-5-carboxamide,
N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide,
(R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide,
(R) -1-ethyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide,
N- (1-ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide,
N- (1-ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide,
N- (1-ethyl-1H-octahydroazonin-3-yl) -6-methoxy-1H-benzo-triazole-5-carboxamide,
(R) -N- (1-cyclopropylmethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide and
(R) -N- (1-cyclopropylmethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide.

In particular, compounds of formula (I) in which R ¹ is ethyl and R ² is hydrogen or methyl are most preferred.

 Preferred in terms of configuration are those compounds of formula (I) wherein the configuration of substituents on the carbon atom bonded to the N atom of the amide radical is racemic (RS) or optically active (R), in particular the latter being more preferred.

 As for the azacycloalkane ring, a 7-, 8- or 9-membered ring is suitable, although a 7-membered ring is particularly preferred, i.e. compounds of formula (I) in which n is 1 are preferred.

Of the above compounds, the following compounds and their pharmaceutically acceptable acid addition salts are particularly preferred:
(R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide (hereinafter referred to as compound 7) and
(R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide (hereinafter referred to as compound 2).

In addition to the compounds listed above, the following compounds and their pharmaceutically acceptable acid addition salts may be given as specific examples of other preferred compounds included in this invention:
(R) -N- (1-ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide,
(R) -N- (1-ethyl-1H-octahydroazonin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide,
(R) -N- (1-ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide and
(R) -N- (1-ethyl-1H-octahydroazonin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide.

 The compounds of this invention can be obtained, for example, by the following methods.

(в которой R^2a обозначает водород, метил, этил или аминозащитную группу)
или их реакционноспособных производных с соединениями, представленными формулой (IV) ниже:

[в которой R¹, n и волнистая линия имеют значения, принятые для формулы (I)].Method (a)
Compounds of formula (I) can be prepared by reacting compounds represented by formula (III) below:

(in which R ^2a is hydrogen, methyl, ethyl or an amino protecting group)
or their reactive derivatives with compounds represented by formula (IV) below:

[in which R ¹ , n and the wavy line have the meanings adopted for formula (I)].

In this case, when R ^2a in the formula (III) is an amino protecting group, the reaction product must then be hydrolyzed or hydrogenolysed to convert R ^2a to a hydrogen atom in order to obtain a compound of formula (I). The interaction of compounds of formula (III) with compounds of formula (IV) can be carried out by the well-known amidation reaction.

Examples of reactive derivatives of compounds of formula (III) include lower alkyl esters (including methyl ester), active esters, acid anhydrides and acid halides (including acid chloride) [when a compound of formula (III) is used in which R ^2a represents a hydrogen atom, acid anhydrides and acid halides are excluded]. Specific examples of active esters include p-nitrophenyl ether, pentachlorophenyl ether, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzothiazole ester, 8-hydroxyquinoline ester, 2-hydroxyphenyl ether and 2-hydroxy-4,5- dichlorophenyl ether. As the acid anhydride, symmetric acid anhydride or mixed acid anhydride is used, specific examples of the latter include anhydrides mixed with alkyl chloroformates such as ethyl chloroformate or isobutyl chloroformate; anhydrides mixed with aralkyl chloroformates, such as benzyl chloroformate; anhydrides mixed with aryl chloroformates such as phenylchloroformate; and anhydrides mixed with alkanoic acids such as isovaleric acid and pivalic acid.

As amino protecting groups that can serve as R ^2a , protecting groups which can be removed by hydrolysis or hydrogenolysis can be used, examples thereof include lower alkanoyl, trifluoroacetyl, lower alkoxycarbonyl, optionally substituted benzyl and optionally substituted benzyloxycarbonyl, acetyl is particularly preferred .

 When the compounds of formula (III) are used per se, the reaction can be carried out in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide-hydrochloride, N, N'-carbonyldiimidazole , N, N'-carbonyldisuccinimide, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl azide and propanphosphonic anhydride. When N, N'-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride is used as a condensing agent, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-1,2 , 3-benzotriazin-4- (3H) -one, N-hydroxy-5-norbornene-2,3-dicarboxyimide or the like.

The interaction of such compounds of formula (III) or their reactive derivatives with compounds of formula (IV) is carried out either in a solvent or in the absence of a solvent. The solvents used should be appropriately selected according to the type of starting compound, and so on, they include: aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride and chloroform; alcohols such as ethanol and isopropyl alcohol; ethyl acetate, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, ethylene glycol and water. These solvents can be used both individually and as a mixture of several types of solvents. If desired, this reaction is carried out in the presence of a base, specific examples of the base include: an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal bicarbonate such as sodium bicarbonate and potassium bicarbonate; and organic bases such as triethylamine, tributylamine, diisopropylethylamine and N-methylmorpholine. An excess of the compound of formula (IV) may also act as a base. The reaction temperature varies depending on the type of starting compounds, etc., but is usually in the range of from about -30 ^° C to 200 ^° C, preferably from about -10 ^° C to 150 ^° C.

When compounds of formula (III) in which R ^2a is an amino protecting group, for example lower alkanoyl, trifluoroacetyl, lower alkoxycarbonyl or optionally substituted benzyloxycarbonyl, are reacted with compounds of formula (IV) to form compounds of formula (I) in which R ^2a is the corresponding a protective group, the products can be hydrolyzed to be converted into compounds of formula (I) in which R ² is hydrogen.

The hydrolysis reaction can be carried out essentially by known methods, for example, by reacting the product with water in a suitable solvent in an acidic or basic medium. As solvents, for example, alcohols such as methanol, ethanol, isopropyl alcohol or the like, dioxane, water or liquid mixtures thereof can be used. Specific examples of the acid used to create the acidic medium include inorganic acids such as hydrochloric, hydrobromic and sulfuric acids; organic acids such as formic, acetic, propionic and oxalic acids; and silica gel. When a compound of formula (III) is used in which R ^2a is an acetyl group, the use of silica gel readily cleaves the acetyl group, turning R ² into a hydrogen atom. Specific examples of bases for creating an alkaline medium include an alkali metal hydroxide such as sodium or potassium hydroxide; and an alkali metal carbonate such as sodium or potassium carbonate. The reaction temperature is usually in the range from about 20 ^o C to 100 ^o C.

When a compound of formula (III) in which R ^2a denotes, along with the above examples of amino protecting groups, an optionally substituted benzyl or benzyloxycarbonyl group, reacts with a compound of formula (IV) to form a compound of formula (I) in which R ^2a denotes the corresponding a protective group, the hydrogenolysis of the product can convert such R ² to hydrogen. Hydrogenolysis can be carried out mainly in a known manner, for example, by reacting the product with hydrogen in a suitable solvent in the presence of a catalyst such as palladium-on-carbon, Raney nickel, etc. Alcohols such as methanol or ethanol can be used as solvents. , acetic acid, dioxane, tetrahydrofuran, water or their liquid mixtures. The reaction temperature is usually used in the range of from about 0 ^° C. to about 80 ^° C. The reaction is carried out at normal or elevated pressure.

Compounds of formula (III) in which R ^2a is hydrogen or an amino protecting group (lower alkanoyl group, trifluoroacetyl group, lower alkoxycarbonyl group or optionally substituted benzyloxycarbonyl group) and their reactive derivatives can be obtained by the method described, for example, in JP -A-80858/1976 (US patent 4.039.672) or similar methods.

Compounds of formula (III) in which R ^2a is a methyl, ethyl or amino protecting group (optionally substituted with a benzyl group) can be prepared by a process using 4-chloro-2-methoxy-5-nitrobenzoic acid as the starting material, comprising the conversion of this compound to an appropriate, structure-adequate amide using a suitable amine, such as propylamine in Step 1 of Scheme 4 below, introducing a methyl, ethyl or optionally substituted benzyl group into the R ² position and reducing to irradiated product according to the following steps 2 and 3 in Scheme 4, preparation of the corresponding 6-methoxy-1H-benzotriazole-5-carboxamide derivative from this compound according to method (b) described below, and then hydrolysis of the product in a manner known per se.

 Specific examples of processes for preparing compounds of formula (IV) are provided below.

 Those compounds of formula (IV) in which n = 1 can be obtained, for example, by the method illustrated in Scheme 1 below.

[В приведенной выше схеме I Tr обозначает трифенилметильную группу, X обозначает реакционноспособный сложноэфирный остаток спирта, R¹ имеет определенное ранее значение и волнистая линия обозначает рацемическую или оптически активную конфигурацию, как определено ранее].

[In the above scheme, I Tr represents a triphenylmethyl group, X represents a reactive ester residue of an alcohol, R ¹ is as previously defined, and a wavy line indicates a racemic or optically active configuration as previously defined].

Stage 1:
The reaction between the compound of formula (A) and chlorotriphenylmethane is usually carried out in a suitable solvent in the presence of a base. The solvent and base used are the same as those mentioned for method (a) above. The reaction temperature is usually in the range from about -10 ^° C to 150 ^° C, preferably from 0 ^° C to 100 ^° C. As the R and S isomers of formula (A), which are the starting compounds, industrial optically active compounds can be used or an industrial racemic compound may be optically resolved, for example, by the method described in J. Org. Chem., 44, 4841-4847 (1979) or obtained from optically active lysine, for example, by the method described in Synthesis, 1978, 614-616. This method of optical resolution or synthesis of an optically active compound is well known per se.

Stage 2:
Compounds of formula (C) can be prepared by reducing compounds of formula (B) using a metal hydride such as diisobutyl aluminum hydride, lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride or the like. Specific examples of the solvents used include, for example, ethers such as diethyl ether, tetrahydrofuran, etc .; aromatic hydrocarbons such as benzene, toluene, etc .; and halogenated hydrocarbons such as methylene chloride, chloroform, etc. The reaction temperature varies depending on the type of metal hydride used, although usually it remains in the range of about -10 ^° C to 100 ^° C, preferably about 0 ^° C to 50 ^° C.

Stage 3:
The reaction of a compound of formula (C) with an R ¹ - introducing agent represented by the formula R ¹ —X is usually carried out in a suitable solvent in the presence of a base. As the reactive ester alcohol residue denoted by X, for example, halogen atoms such as chlorine, bromine and iodine can be mentioned; lower alkylsulfonyloxy groups such as methanesulfonyloxy; and arylsulfonyloxy groups such as benzenesulfonyloxy. Specific examples of the solvent include: aromatic hydrocarbons such as benzene, toluene; ketones such as acetone, methyl ethyl ketone; ethers such as tetrahydrofuran, dioxane; alcohols such as ethanol, isopropyl alcohol; acetonitrile, chloroform, ethyl acetate, dimethylformamide, dimethyl sulfoxide, and their liquid mixtures. Specific examples of the base used are the same as those listed above for method (a). When X in the R ¹ - introducing agent (R ¹ -X) is chloro or bromo, an alkali metal iodide such as sodium iodide or potassium iodide is added to smoothly carry out the reaction. The reaction temperature varies depending on the type of R ¹ - introducing agent used, although usually it is in the range of from about 0 ^° C to 200 ^° C, preferably from about 80 ^° C to 150 ^° C.

Stage 4:
The reaction in this step is usually carried out in a suitable solvent in the presence of an inorganic acid, such as dilute hydrochloric acid, dilute sulfuric acid, or the like. Specific examples of the solvent used include alcohols, such as methanol, ethanol; ethers such as diethyl ether, tetrahydrofuran; acetone, acetonitrile, ethylene glycol and mixtures of the above fluids. The reaction temperature varies depending on the type of starting compound used, although usually it is in the range of about 0 ^° C. to about 100 ^° C.

The compounds of formula (IV ') can also be obtained when the order of stage 2 of the reduction reaction and stage 3 of the reaction of introducing R ^{1 are} reversed in the above Scheme 1. This means that the introduction of R ¹ into the compound of formula (B) ( step 2 ′) and subsequent reduction (step 3 ′) can lead to the corresponding compound of formula (D). In the reaction of this step 2 ′, it is preferable to use a strong base, such as sodium hydride, instead of the base described for method (a). In addition, it is desirable to use, for example, sodium bis (2-methoxyethoxy) -aluminohydride in the 3 ′ reduction reaction.

(в которой Y обозначает атом галогена, n' равно 2 или 3 и R¹ и X имеют принятые ранее значения).Compounds of formula (IV) in which n is 2 or 3 are prepared, for example, by the method illustrated by Scheme 2 below:

(in which Y represents a halogen atom, n 'is 2 or 3, and R ¹ and X are as previously defined).

 Stage 1 in the above scheme 2 can be performed in a manner analogous to stage 2 ', a modified method of the approach adopted in illustrative scheme 1, using, for example, commercially available 2-azacyclooctanone or 2-azacyclononanone. Halogenation of stage 2 can be performed, for example, according to the method described in J.Am. Chem. Soc. 80, 6233-6237 (1958). Steps 3 and 4 can be performed, for example, following the method described in Helv.Chim.Acta, 41, 181-188 (1958).

(в которой R¹, Tr и n - имеют принятые выше значения).The compounds of formula (IV) can also be obtained by the method illustrated by the following scheme 3:

(in which R ¹ , Tr and n - have the above values).

 Step 1 of the above scheme 3 is carried out in a suitable solvent, bringing the compound of formula (E) to an anionic form under the influence of a strong base and then reacting it with dry ice.

 The conversion of the carboxyl group to the amino group in step 2 can be accomplished by reacting the compound of formula (F) with ethyl chloroformate and sodium azide in a suitable solvent, followed by heating the resulting acyl azide and exposing the acid to an isocyanate product. Triphenylmethylation in step 3, reaction in step 4, and removal of the triphenylmethyl group in step 5 can be performed in a manner analogous to steps 1, 2, and 4 of Scheme 1, respectively.

 The starting compounds of formula (E) can be prepared by the method of Step 1 of Scheme 2 using, for example, a starting compound of α-caprolactam, 2-azacyclooctanone or 2-azacyclononanone.

 According to the method illustrated by Scheme 1, the configuration of the starting compound (A) is converted to the final product of the formula (IV '). Whereas the final products (IV``) or (IV '' ') obtained by the method of Scheme 2 or Scheme 3 are racemic. The racemic compounds of formula (IV) can be separated into two optical isomers by methods known per se. For example, such a compound of formula (IV) is treated with optically active acid to form diastereomer salts or amides, which are separated by fractional recrystallization or column chromatography, and then converted to free bases.

 Compounds of the above formula (IV) are new.

(в которой R¹ и n имеют приведенные выше значения), используются в качестве новых промежуточных соединений формулы (I), имеющих R - конфигурацию, соединения, представленные ниже формулой (IVb):

(в которой R¹ имеет приведенные выше значения) являются особенно предпочтительными.Compounds represented by the following formula (IVa) and having an R configuration:

(in which R ¹ and n have the above meanings), are used as new intermediates of formula (I) having an R - configuration, compounds represented by formula (IVb) below:

(in which R ¹ has the above meanings) are particularly preferred.

(в которой R¹, R², n и волнистая линия имеют приведенные выше значения) для образования бензотриазольного цикла.Method (b)
Compounds of formula (I) can be prepared by diazotization of compounds of formula (V) below:

(in which R ¹ , R ² , n and the wavy line are as defined above) to form a benzotriazole ring.

The ring closure reaction (benzotriazole ring formation reaction) leading to the formation of compounds of formula (I) by diazotization of compounds of formula (V) is carried out under diazotization conditions commonly used for aromatic amines. As diazotizing agents, for example, nitrous acid alkyl esters such as sodium nitrite, tert-butyl nitrite and isoamyl nitrite can be used. Closing a loop using nitrous acid is usually accomplished by first adding an excess of inorganic acid (e.g. hydrochloric acid) or organic acid (e.g. acetic acid) to an aqueous solution of a compound of formula (V) or its acid addition salt, and then adding an aqueous nitrite solution sodium. The reaction temperature is usually kept in the range of about -20 to 60 ^° C, preferably about 0 ^° C to 25 ^° C. The ring closure reaction using nitrous acid alkyl ester is usually carried out in a suitable solvent by reacting a compound of formula (V) or a salt thereof acid addition (e.g., hydrochloride, acetate) with an alkyl ester of nitrous acid. Examples of a suitable solvent include methanol, acetic acid, acetic acid-dioxane, 1,2-dimethoxyethane, tetrahydrofuran, acetone and methylene chloride. The reaction temperature is usually maintained in the range of from about 0 ^° C to 100 ^° C, preferably from about 30 ^° C to 80 ^° C.

 The starting compounds represented by formula (V) can be prepared, for example, by a method as illustrated in Scheme 4 below.

(в которой Z обозначает атом галогена и R², Az и волнистая линия имеют приведенные выше значения).

(in which Z represents a halogen atom and R ² , Az and the wavy line have the above meanings).

Stage 1:
The interaction of compounds of formula (J) or their reactive derivatives with compounds of formula (IV) is carried out in a manner analogous to method (a). Source compounds
formulas (J) can be obtained, for example, by the method described in Helv. Chim.Acta. 40, 369-372 (1957).

Stage 2:
The interaction of compounds of formula (K) with compounds represented by the formula; H ₂ NR ² , performed without solvent or in an adequate solvent.

Examples of the solvent used include alcohols such as methanol and ethanol; dimethylformamide, dimethyl sulfoxide and water. The reaction temperature is usually used in the range of from about 0 ^o C to 150 ^o C.

Stage 3:
The recovery of compounds of formula (L) is carried out in a conventional manner. For example, a compound of formula (L) may be treated in a suitable solvent with a reducing agent. Specific examples of the reducing agents used include combinations of metals (e.g., tin, zinc, iron) or metal salts (e.g., tin chloride) with acids (e.g., hydrochloric acid, acetic acid), although iron or tin chloride alone can be used in as a reducing agent. Recovery can also be performed by hydrogenation of compounds of formula (L) in a suitable solvent in the presence of a catalyst. Specific examples of the catalyst include palladium carbon, Raney nickel, and platinum oxide. The solvent should be selected according to the nature of the reducing agent used or the type of reduction method used. Alcohols such as methanol or ethanol are usually used as solvents; ethyl acetate, acetone, acetic acid, dioxane, water or their liquid mixtures. The reaction temperature also varies depending on the reducing agent or reduction methods used in each case, although usually it is in the range of from about 10 ^° C to 100 ^° C, and in the case of catalytic reduction, the preferred range is from about 10 ^° C to 50 ^° C.

 Thus obtained compounds of formula (V) can be used as a starting compound for the method of obtaining (b) without isolation and purification.

[в которой R^3a обозначает амино-защитную группу (например, необязательно замещенный бензил или необязательно замещенный бензилоксикарбонил), и R¹, n и волнистая линия имеют приведенные выше значения].Method (c):
Compounds of formula (I) in which R ² represents a hydrogen atom can also be prepared by hydrogenolysis of compounds represented by formula (IIa) below:

[in which R ^3a is an amino protecting group (for example, optionally substituted benzyl or optionally substituted benzyloxycarbonyl), and R ¹ , n and the wavy line are as defined above].

Hydrogenolysis can be accomplished in a conventional manner, for example, by reacting the compounds either with hydrogen in a suitable solvent and in the presence of a catalyst such as palladium-on-carbon, Raney nickel or the like, or with a hydrogen donor (e.g., ammonium formate, cyclohexene) in the presence of a catalyst such as palladium-carbon. As a solvent, for example, alcohols such as ethanol or methanol are used; water, acetic acid, dioxane or tetrahydrofuran. The reaction temperature is usually used in the range of from about 0 ^° C. to about 80 ^° C. The reaction is carried out at normal or elevated pressure.

Compounds of formula (IIa) in which R ^3a is an optionally substituted benzyl group can be prepared by method (b) using, as starting compounds in Scheme 4, those compounds of formula (V) in which R ² is, for example, optionally substituted benzyl a group. The starting compounds (V) can be obtained by the method illustrated by Scheme 4. In this case, the reduction reaction of step 3 is preferably carried out using a combination of a metal or a metal salt of an acid, or iron, or tin chloride.

Compounds of formula (IIa) in which R ^3a is an optionally substituted benzyloxycarbonyl group can be prepared by method (a) using, as starting compounds, those compounds of formula (III) in which R ^2a is an optionally substituted benzyloxycarbonyl group, which in its the queue can be obtained, for example, by the method described in JP-A-80858/1976 (US patent 4.039.672) or by methods similar to this.

[в которой R^3b обозначает амино-защитную группу (например, низший алканоил, трифторацетил, низший алкоксикарбонил или необязательно замещенный бензилоксикарбонил), и R¹, n и волнистая линия имеют приведенные выше значения].Method (d)
Compounds of formula (I) in which R ² represents a hydrogen atom can also be prepared by hydrolysis of compounds of formula (IIb) below:

[in which R ^3b represents an amino protecting group (for example, lower alkanoyl, trifluoroacetyl, lower alkoxycarbonyl or optionally substituted benzyloxycarbonyl), and R ¹ , n and the wavy line are as defined above].

The hydrolysis reaction can be carried out in a substantially known manner, for example, by contacting the starting compound (IIb) with water in a suitable solvent, in an acidic or alkaline medium. As the solvent, for example, alcohols such as methanol, ethanol, isopropyl alcohol and the like can be used; dioxane, water or mixtures thereof. Specific examples of the acid used to create the acidic environment include mineral acids such as hydrochloric, hydrobromic and sulfuric acids; organic acids such as formic, acetic, propionic and oxalic acid; and silica gel. When a compound of formula (IIb) contains an acetyl group as R ^3b , the use of silica gel makes it easy to cleave the acetyl group and turn this compound into a compound of formula (I) in which R ² represents a hydrogen atom. Specific examples of the base used to create the alkaline medium include an alkali metal hydroxide such as sodium or potassium hydroxide; and an alkali metal carbonate such as sodium carbonate, potassium carbonate, etc. The reaction temperature is usually maintained in the range from about 20 ^o C to 100 ^o C.

Compounds of formula (IIb), which are intermediates of the present invention, can be prepared by the previously described method (a) using as starting compounds those compounds of formula (III) in which R ^2a is lower alkanoyl, trifluoroacetyl, lower alkoxycarbonyl or optionally substituted benzyloxycarbonyl, which in turn can be obtained, for example, by the method described in JP-A-80858/1976 (US patent 4.039.672), or similar methods.

 According to methods (a), (b), (c) and (d), the configuration of the starting compounds of the formulas (IV), (V), (IIa) and (IIb) is maintained during the formation of the compounds of the formula (I). Therefore, it is preferable to obtain the compounds of formula (I) having a given configuration, to use the starting compounds having the appropriate configuration. In addition, it is possible to use the racemic starting compound to prepare the racemic compound of formula (I), which can then be optically resolved by conventional methods.

 Compounds obtained by the above methods can be isolated and purified by conventional methods such as chromatography, recrystallization, reprecipitation, etc.

 The compounds of formula (I) and compounds of formulas (IIa) and (IIb) are obtained in the form of a free base or an acid addition salt, which depends on the type of the starting compounds, the reaction conditions and the treatment. Acid addition salts can be converted to the free base by treating them with a base such as alkali metal carbonate or alkali metal hydroxide. Whereas the free bases can be converted to the acid addition salt form by treating them with various acids according to conventional methods.

 The following are test results of representative compounds of this invention and metoclopramide hydrochloride monohydrate (metoclopramide) (Compound A), an industrial agent for improving contractility of the gastrointestinal tract, and the pharmacological effects of the compounds of the invention are discussed.

 First, a list of compounds of this invention used in pharmacological tests is given, with an indication of their structure and compound numbers.

The compound of example 1 (compound 1)
N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide.

Соединение примера 2 (соединение 2)
(R)-N-(1-этил-1Н-гексагидроазепин-3-ил)-6-метокси-1-метил-1Н- бензотриазол-5-карбоксамид

Соединение примера 4 (соединение 4)
1-этил-N-(1-этил-1H-гeкcaгидpoaзeпин-3-ил)-6-мeтoкcи 1Н- бензотриазол-5-карбоксамид

Соединение примера 5 (соединение 5)
(R)-1-этил-N-(1-этил-1Н-гексагидроазепин-3-ил)-6-метокси-1Н- бензотриазол-5-карбоксамид

Соединение примера 6 (соединение 6) N-(1-этил-1Н- гексагидроазепин-3-ил)-6-метокси-1Н-бензотриазол-5-карбоксамид

Соединение примера 7 (соединение 7a) N-(1-этил-1Н- гексагидроазепин-3-ил)-6-метокси-1H-бензотриазол-5-карбоксамид

(соединение 7b)
(R)-N-(1-этил-1Н-гексагидроазепин-3-ил)-6-метокси-1Н-бензотриазол- 5-карбоксамид•3/2 фумарат
Соединение примера 9 (соединение 9)
N-(1-этил-1Н-гептагидроазоцин-3-ил)-6-метокси-1H-бензотриазол- 5-карбоксамид

Соединение примера 10 (соединение 10)
N-(1-этил-1Н-октагидроазонин-3-ил)-6-метокси-1H-бензотриазол- 5-карбоксамид

Соединение примера 11 (соединение 11)
N-(1-циклопропилметил-1Н-гексагидроазепин-3-ил)-6-метокси-1Н- бензотриазол-5-карбоксамид

Соединение примера 12 (соединение 12)
(R)-N-(1-циклопропилметил-1Н-гексагидроазепин-3-ил)-6-метокси-1Н- бензотриазол-5-карбоксамид

Соединение примера 13 (соединение 13)
(R)-N-(1-циклопропилметил-1Н-гексагидроазепин-3-ил)-6-метокси-1- метил-1Н-бензотриазол-5-карбоксамид

Соединение примера 14 (соединение 14)
N-(1-этил-1Н-гептагидроазоцин-3-ил)-6-метокси-1-метил-1Н- бензотриазол-5-карбоксамид

Соединение примера 15 (соединение 15)
N-(1-этил-1Н-октагидроазонин-3-ил)-6-метокси-1-метил-1Н- бензотриазол-5-карбоксамид

Соединение примера 3 (соединение 3)
(S)-N-(1-этил-1Н-гексагидроазепин-3-ил)-6-метокси-1-метил-1Н- бензотриазол-5-карбоксамид

Соединение примера 8b (соединение 8b)
(S)-N-(1-этил-1Н-гексагидроазепин-3-ил)-6-метокси-1Н-бензотриазол- 5-карбоксамид•3/2 фумарат

Соединение A
Моногидрат гидрохлорида 4-амино-5-хлор-N-[2-(диэтиламино) этил]-2-метоксибензамида [общее название: метоклопрамид; см., например, Merck Index, 11th ed. 6063 (1989)]

Эксперимент 1
Ингибирующее воздействие на апоморфин-индуцируемую рвоту
Группу из 3-4 собак (Гончая, 8-15 кг) используют для исследования ингибирующих воздействий испытуемых соединений на апоморфин-индуцируемую рвоту, согласно способу Chen and Ensor [cf.J.Pharmacol. Exp. Ther., 98 245-250 (1950)].

The compound of example 2 (compound 2)
(R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide

The compound of example 4 (compound 4)
1-ethyl-N- (1-ethyl-1H-hexahydrazine-3-yl) -6-methoxy 1H-benzotriazole-5-carboxamide

The compound of example 5 (compound 5)
(R) -1-ethyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide

The compound of example 6 (compound 6) N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide

The compound of example 7 (compound 7a) N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide

(compound 7b)
(R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide • 3/2 fumarate
The compound of example 9 (compound 9)
N- (1-ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide

The compound of example 10 (compound 10)
N- (1-ethyl-1H-octahydroazonin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide

The compound of example 11 (compound 11)
N- (1-cyclopropylmethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide

The compound of example 12 (compound 12)
(R) -N- (1-cyclopropylmethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide

The compound of example 13 (compound 13)
(R) -N- (1-cyclopropylmethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide

The compound of example 14 (compound 14)
N- (1-ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide

The compound of example 15 (compound 15)
N- (1-ethyl-1H-octahydroazonin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide

The compound of example 3 (compound 3)
(S) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide

Compound of Example 8b (Compound 8b)
(S) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide • 3/2 fumarate

Compound A
4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-methoxybenzamide hydrochloride monohydrate [common name: metoclopramide; see, for example, Merck Index, 11th ed. 6063 (1989)]

Experiment 1
Inhibitory effect on apomorphine-induced vomiting
A group of 3-4 dogs (Hound, 8-15 kg) is used to study the inhibitory effects of test compounds on apomorphine-induced vomiting, according to the method of Chen and Ensor [cf. J. Pharmacol. Exp. Ther., 98,245-250 (1950)].

 Test compounds, dissolved or suspended in a 0.5% tragacanth solution, are administered orally two hours before subcutaneous administration of apomorphine hydrochloride (0.3 mg / kg). Then, within one hour, the number of bouts of vomiting is counted. The number of attacks of vomiting in the compound-treated group is compared with the number of attacks in the corresponding control (non-dose) group and the percent inhibition is calculated. The results are shown in table 1.

 From table 1 it is obvious that almost all of the test compounds of this invention show equal or greater than metoclopramide - hydrochloride monohydrate (compound A) activity in the inhibition of apomorphine-induced vomiting.

Experiment 2: Activity that enhances the contractility of the gastrointestinal tract
The tests are carried out according to the method of Scarpignato et al. [cf. Arch.Int. Pharmacodyn., 246, 286-294 (1980)].

 Male rats weighing 130-150 g, kept hungry for 18 hours before the start of the experiment and give orally 1.5 ml of test breakfast (phenol red 0.05% in a 1.5% aqueous solution of methylcellulose). Fifteen minutes after the introduction of breakfast, the stomach is removed and the amount of red phenol remaining in the stomach is measured. Test compounds, dissolved or suspended in a 0.5% tragacanth solution, are given orally 60 minutes before a test breakfast. The degree of contractility of the gastrointestinal tract is calculated by the amount of red phenol remaining in the stomach, and the activity of the test compounds is expressed through an increase in the degree of contractility compared with the control. The number of test animals is 4 for the test compounds of this invention and 5 for compound A used for comparison. The results are shown in table 2.

 As follows from table 2, each test compound according to this invention shows equal or greater than metoclopramide hydrochloride monohydrate (compound A) activity in enhancing the contractility of the gastrointestinal tract.

Experiment 3: Effects on contractility of the gastrointestinal tract delayed by cholecystokinin or morphine
The test is carried out according to the method of Scarpignato et al. [Cf. Arch.Int.Pharmacod yn., 246, 286-294 (1980)].

 Male Wistar rats weighing 130-150 g were kept hungry for 18 hours before the start of the experiment and were given orally 1.5 ml of test breakfast (phenol red 0.05% in 1.5% aqueous solution of methylcellulose). Fifteen minutes after the introduction of breakfast, the stomach is removed and the amount of red phenol remaining in the stomach is measured.

 The test compounds, 10, 30 or 100 mg / kg each, dissolved or suspended in a 0.5% solution of tragacanth, are given orally 60 minutes before a test breakfast. The contractility of the gastrointestinal tract is slowed by subcutaneous administration of cholecystokinin 3 mg / kg or morphine 3 mg / kg 5 minutes before phenol red administration. The number of animals used was 5-10. The results are shown in table 3.

 Test compound 2 (compound of Example 2) according to this invention at doses of 300-100 mg / kg significantly improves the contractility of the gastrointestinal tract delayed by cholecystokinin.

 Test compound 7b (compound of Example 7b) of the present invention at doses of 10, 30 or 100 mg / kg significantly improves gastrointestinal contractility slowed by cholecystokinin or morphine and exhibits excellent activity enhancing gastrointestinal contractility (gastroprokinetic activity) ) compared with bowel movement delayed by cholecystokinin and morphine at each dose. On the other hand, metoclopramide hydrochloride monohydrate (compound A) at doses of 10, 30 or 100 mg / kg does not show an improvement in activity with respect to delayed bowel movement caused by cholecystokinin or morphine.

Experiment 4
Effects on the contractility of the gastrointestinal tract in conscious dogs.

 Four healthy beagle dogs per group, both sexes weighing 10-12 kg, are anesthetized by intravenous injection of sodium pentobarbital (Nembutal, 30 mg / kg body weight), and the abdominal cavity is opened under aseptic conditions. According to the method for measuring round muscle contraction, extraluminary force sensors are sutured into the serous muscle layer of the gastric cavity, 3 cm proximal to the pyloric ring, duodenum, jejunum, midgut and ileum, according to the method of Ito et al. [cf. Gastrointerol. Japan 12, 275-283 (1977)].

 For intragastric (i.g.) administration of drugs, a sylastic tube (Fr, size 6.5) is inserted into the cavity of the organ suffering from gastritis and the tube is fixed on the adjacent serous membrane. The lead wires of these sensors and the tube for examining the stomach are removed from the abdominal cavity and then passed through a skin incision made between the shoulder blades. After surgery, a protective apron is put on the dog to protect the lead wires and the silastic tube. Dogs are placed in isolated experimental cages and give food up to 10 am. (until noon), water is given unlimitedly.

 Test compounds of 3 and 10 mg / kg are suspended in a 0.5% solution of tragacanth and administered i.g. through the inside of the silastic tube.

 Compounds 2 and 7b of this invention at doses of 3 and 10 mg / kg cause contractions similar to internal digestive movements in the feeding state in conscious dogs. Thus, it was found that the test compounds exhibit significant activity, enhancing the contractility of the gastrointestinal tract (gastroprokinetic activity). In contrast, compound A does not at all cause a reduction in digestive movement.

 Experiment 5 The effect of inhibition of explorative activity.

A group of 5 male mice was used (Std-ddy strain 20-25 g). Two hours after oral administration of the test compounds in the form of a 0.5% tragacanth solution or suspension, the mice are placed separately in a test box (23 x 35 x 30 cm) on an Animex activity counter (Farad Co.). After that, immediately start the activity count and continue for three minutes. The average calculated value for the compound-treated group is compared with the same value for the corresponding control (not-dosed) group, and the% inhibition and 50% inhibitory dose (ID ₅₀ ) are calculated by the method.

 The results are shown in table 4.

 As follows from table 4, each test compound according to this invention shows a much lower effect of inhibition of explorative ability than metoclopramide hydrochloride monohydrate (compound A). This result leads to the conclusion that the compounds of this invention have a significantly lower suppression of the central nervous system in comparison with the effects of compound A.

 Experiment 6: Acute toxicity.

A group of 5 male mice was used (Std-ddy strain 25-30 g). The test compound is administered orally to the test animal in the form of a 0.5% tragacanth solution or suspension, and 7 days after the administration of the test compounds, the death of the animals is observed and a 50% lethal dose (LD ₅₀ ) is determined.

 The results are shown in table. 5.

 As can be seen from the above test results, the compounds of formula (I) according to this invention and their pharmaceutically acceptable salts of acid addition have both a significant inhibitory effect against vomiting and activity that enhances the contractility of the gastrointestinal tract (gastroprokinetic activity) along with low CNS - depressant activity and low toxicity, and, therefore, are useful as agents that enhance the contractility of the gastrointestinal tract (gastroproc ) for the treatment and prevention of various gastrointestinal functional disorders associated with various diseases and medications: for example, diseases such as: anorexia, nausea, vomiting, fullness of the stomach, discomfort of the upper gastrointestinal tract, abdominal pain, heartburn and belching, which are observed in acute and chronic gastritis, esolaphage reflux, gastric and duodenal ulcer, gastroneurosis, gastroptosis, paralytic bowel obstruction after surgery and, senile bowel obstruction, dumping syndrome, scleroderma, diabetes, violation of the esophagus and bile ducts, periodic puerile vomiting, upper respiratory tract infections: for example, mucous colitis, constipation, diarrhea in infants: and for example, nausea and vomiting accompanying anticancer drugs or levodone preparations, or after x-ray exposure.

 Of the compounds of this invention, compounds 2, 7a and 7b show a particularly high activity in enhancing the contraction of the gastrointestinal tract.

 Pharmaceutical preparations can be administered orally, parenterally or rectally. The clinical dose varies depending on the type of compounds, route of administration, severity of disease, age of patients, and the like, but is usually used in the range of 0.01 to 10 mg / kg / day, preferably 0.1 to 3 mg / kg / day .

 When using the compounds of formula (I) or their pharmaceutically acceptable acid addition salts for the medical use described above, they are usually administered to the patient in the form of pharmaceutical formulations, mixed with carriers commonly used to make medical formulations and not reacting with the compounds of this invention. More specifically, for example, carriers such as lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized starch, sucrose, magnesium aluminum metasilicate, synthetic aluminosilicate, microcrystalline cellulose, sodium carboxymethyl calcyl, can be named β-carboxymethyl cellulose, ion exchange resin, methyl cellulose, gelatin, acacia juice, pullulan, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, poly vinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, low-viscosity anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, veegam, carboxyvinyl polymer, titanium dioxide, sorbitan fatty acid ester, sodium lauryl sulfide glycerides, glycerides, glycerides, glycerides, glycerides, glycerides , glycerol gelatin, polysorbate, macrogol, vegetable oils, paraffin, water, propylene glycol, ethanol, sodium chloride, sodium hydroxide, hydrochloric acid, citric acid, benzyl alcohol, glutamic acid, glyc H, methyl parahydroxybenzoate, propyl parahydroxybenzoate and the like.

 The pharmaceutical compositions can be taken in any formulation, such as tablets, capsules, granules, powders, syrups, suspensions, injections, poultices, suppositories and the like, obtained by conventional methods. Liquid formulations may be taken in such forms that they are dissolved or suspended in water or other suitable medium before use. Tablets and granules may be coated by methods that are well known per se.

The compounds of this invention represented by formula (I) in which R ² is hydrogen exhibit good solubility in water and are therefore particularly suitable for liquid preparations.

 These preparations may contain at least 0.01% of a compound of formula (I) of the present invention or a pharmaceutically acceptable acid addition salt thereof, preferably in a ratio of between 0.1 and 70%. The preparations may also contain other therapeutically acceptable components.

The best embodiment of the invention
The invention is further disclosed more specifically by standard examples and experimental examples, it is understood that they do not limit the scope of the invention. Identification of the obtained compounds was carried out on the basis of data such as elemental analysis, mass spectrum, UV spectrum, IR spectrum, NMR spectrum, etc.

In the following standard and experimental examples, the following notation is sometimes used for ease of recording:
[Solvent for recrystallization]
A: ethanol
E: diethyl ether
[Deputy]
Me: methyl
Et: ethyl
Δ: cyclopropyl
Ph: phenyl
NMR
J: communication constant
s: singlet
d: doublet
dd: double doublet
t: triplet
sq: quartet
m: multiplet
broad. c: extended singlet
[Other notation]
her: enantiomeric excess
Example 1 [reaction according to method (b)]
Preparation of N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide (compound 1):
To 40 ml of an aqueous solution containing about 3.0 g of 5-amino-N - (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylaminobenzamide obtained in the following standard example 4, add 5 ml of acetic acid. Then the solution is cooled to 5 ^o C, add 10 ml of an aqueous solution containing 0.8 g of sodium nitrite, and then stirred for one hour at the same temperature. The reaction mixture was made basic with aqueous sodium hydroxide and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give an oily residue. The oil is subjected to silica gel column chromatography, after which it is eluted and purified with a mixture of chloroform-methanol (9: 1). The resulting solid was recrystallized from toluene-n-hexane to give 2.3 g of the title compound, mp. 103-104 ^o C.

Example 2 [reaction according to method (b)]
Preparation of (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide (compound 2):
An aqueous solution of acetic acid containing (R) -5-amino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylaminobenzamide, prepared in Standard Example 5 below, is cooled to 5 ^° C and 50 ml of an aqueous solution containing 6.6 g of sodium nitrite are added dropwise. The mixture was stirred for one hour at this temperature and then for two hours at room temperature. The reaction mixture was made basic with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give an oily residue. The oil was subjected to silica gel column chromatography and then eluted and purified with a mixture of chloroform-methanol (9: 1). The resulting solid was recrystallized from toluene-n-hexane to give 26.7 g of the title compound, mp. 118-120 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{27}}{\text{D}}$ - 70.6 ^o (s = 1.0, ethanol).

Example 3 [reaction according to method (b)]
Preparation of (S) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide (compound 3):
The reaction and processing is carried out in a manner analogous to example 2, using an aqueous solution of (S) -5-amino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylaminobenzamide, obtained below in the standard example 6. The resulting product was recrystallized from toluene-n-hexane to give the title compound, mp. 119-120 ^o C.

Example 4 [reaction according to method (b)]
Preparation of 1-ethyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide (compound 4):
The reaction and treatment are carried out according to the method of example 1, using an aqueous solution of 5-amino-N- (1-ethyl-1H-hexahydro-azepin-3-yl) -4-ethylamino-2-methoxybenzamide, obtained below in standard example 7. The resulting the product was recrystallized from toluene-n-hexane to give the title compound, mp 84-85 ^o C.

Example 5 [reaction according to method (b)]
Preparation of (R) -1-ethyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide (compound 5);
The reaction and processing are carried out according to the method of example 1, using an aqueous solution of (R) -5-amino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -4-ethylamino-2-methoxybenzamide obtained according to standard example 8. The product is obtained in the form of an oil: mass spectrum (m / z): 346 (MH ⁺ ).

Example 6 [reaction according to method (a)]
Preparation of N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide (compound 6):
To 10 ml of a dimethylformamide solution containing 0.85 g of 6-methoxy-1H-benzotriazole-5-carboxylic acid, 0.78 g of N, N'-carbonyldiimidazole was added and stirred for 6 hours at room temperature. 0.75 g of 3-amino-1-ethyl-1H-hexahydroazepine was added to the reaction mixture, and then stirred for 14 hours at room temperature. After termination of the reaction, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography using elution and purification with chloroform-methanol (10: 1). The resulting product was recrystallized from ethanol-diethyl ether to give 1.3 g of the title compound, mp. 156-158 ^o C.

¹ H-NMR spectrum (CDCl ₃ , δ ppm): 1.09 (3H, t, J = 7 Hz), 1.5-2.1 (6H, m), 2.5-3.1 (6H, m), 3.83 (3H , s), 4.4 (1H, m), 6.4 (1H, broad s), 7.07 (1H, s), 8.05 (1H, d, J = 8 Hz), 8.78 (1H, s).

Example 7 [reaction according to method (a)] and [(reaction according to method (d)]
Preparation of (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide (compound 7a):
a) [reaction according to method (a)]
To 150 ml of a dimethylformamide solution containing 10 g of 6-methoxy-1H-benzotriazole-5-carboxylic acid, 9.0 g of N, N'-carbonyldiimidazole was added and stirred for 6 hours at room temperature. To the reaction mixture was added 8.8 g of (R) -3-amino-1-ethyl-1H-hexahydroazepine and stirred for 14 hours at room temperature. After termination of the reaction, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluting and purifying with chloroform-methanol (10: 1). The resulting product was recrystallized from diethyl ether-n-hexane to give 12 g of the title compound (compound 7a), mp. 127-128 ^o C.

(a ') The title compound is again recrystallized from ethyl acetate-n-hexane to give the title compound, mp. 142-144 ^o C.

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ - 71.9 ^o (s = 1.0, methanol).

 This compound, in high resolution liquid chromatography (HPLC), has a retention time of 37.2 minutes under the conditions below and it has an optical purity of 99% or higher.

HPLC conditions
HPLC column: SUMICHIRAL OA-4900; 4.6 mm x 250 mm manufactured by Sumitomo Chemical Analysis Center
Mobile phase: n-hexane-methylene chloride-ethanol-trifluoroacetic acid (400: 100: 100: 0.6)
Flow Rate: 1.0 ml / min
temperature: 25 ^o C
detection: 230 nm.

 From the starting material having the R configuration, the compound indicated above in the title with an optical purity of 99% or higher is obtained by HPLC, racemization is not observed. In addition, as shown in Example 8 below, an S-configuration compound with an optical purity of 99% or higher is obtained from the original S-configuration compound, without racemization. These facts clearly show that the configuration of the title compound obtained in this example is R.

(b) The product obtained in step (a) above is treated with fumaric acid to convert it to the corresponding fumarate, which is recrystallized from isopropyl alcohol-methanol to obtain 3/2 fumarate of the compound (compound 7b), mp 131-133 ^o C.

(b ') The product obtained in step (a) above is treated with fumaric acid to convert it to the corresponding fumarate, which is recrystallized from isopropyl alcohol to give 3/2 fumarate of the title compound, mp 162-163 ^o C.

(b '') The product obtained in step (a) above is treated with fumaric acid and converted to the corresponding fumarate, which is recrystallized from ethanol-isopropyl alcohol to obtain 3/2 fumarate • 1/4 hydrate of the title compound, mp . 166-168 ^o C.

(c) A reaction using a compound of formula (III) in which R ² is an acetyl group (amino protecting group)
[reaction according to method (a)]:
To 31.5 g of 1-acetyl-6-methoxy-1H-benzotriazole-5-carboxylic acid, 20.3 g of triethylamine and 400 ml of ethyl acetate were added and the mixture was added dropwise at -7 ^° C to -10 ^° C 17.5 g of ethyl chloroformate. After a further 2-hour stirring at -5 ^° C to -7 ^° C, 80 ml of an ethyl acetate solution containing 22.8 g of (R) -3-amino-1-ethyl-1H-hexahydroazepine and the mixture is stirred for one hour at this temperature and then 16 hours at room temperature. The reaction mixture was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 1000 ml of a mixture of chloroform-methanol (8: 1) and then 180 g of silica gel was added to the solution and subsequently stirred for 16 hours at room temperature.

 Silica gel was removed by filtration and the residue was washed with 1000 ml of a mixture of chloroform-methanol (5: 1). The solvent was evaporated under reduced pressure to obtain 32 g of a crude target product.

Twenty-four (24) g of the crude product obtained above are treated with 2.5-3-fold volume (22.5 g) of fumaric acid and the resulting fumarate is recrystallized from methanol-isopropyl alcohol to obtain 25 g 3/2 fumarate of the title compound, t .pl. 131-133 ^o C.

(d) [reaction according to method (d)]
To 1.85 g of (R) -1-acetyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide obtained in Example 17 below, 55 ml of a mixture of chloroform-methanol (8: 1). Then 18.5 g of silica gel was added and the mixture was stirred for 16 hours at room temperature. Silica gel was removed by filtration and the residue was washed with a mixture of chloroform-methanol (9: 1) containing 1% aqueous ammonia. The solvent was evaporated under reduced pressure to obtain 1.78 g of a crude target product.

Example 8 [reaction according to method (a)]
Preparation of (S) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide (compound 8):
a) Replacing the (R) -3-amino-1-ethyl-1H-hexahydroazepine of Example 7 with the (S) -3-amino-1-ethyl-1H-hexahydroazepine, which is reacted and treated according to the method of Example 7, obtain connection titles.

(b) The product obtained above is treated with fumaric acid and converted to the corresponding fumarate. Recrystallization from isopropyl alcohol gives 3/2 fumarate of the title compound, mp 156-158 ^o C.

 The title compound shows a retention time of 44.0 minutes in HPLC under the assay conditions of Example 7 and has an optical purity of 99% or higher.

(b ') The product obtained in step (a) above is treated with fumaric acid in the same manner as in step (b) above, and the resulting fumarate is recrystallized from ethanol-isopropyl alcohol. Get difumarate • 1/2 hydrate specified in the title compound, so pl. 148-151 ^o C.

Examples 9-12 - reaction according to method (a)
Example 6 is repeated, except that 3-amino-1-ethyl-1H-hexahydroazepines are replaced with the corresponding 3-amino-1-substituted-1-hexahydroazepines.

 In this way receive the compounds shown in table 6.

Пример 13 [реакция по способу (b)]
Получение (R)-N-(1-циклопропилметил-1H-гексаридроазепин-3-ил)- 6-метокси-1-метил-1Н-бензотриазол-5-карбоксамида (соединение 13):
Используя соответствующее исходное соединение, водный раствор (R)-5-амино-N-(1-циклопропилметил-1Н-гексагидроазепин- 3-ил)-2-метокси-4-метиламинобензамид получают, используя реакцию и способ обработки, аналогичные приведенным ниже в примере 18 и стандартных примерах 1 и 4. Этот раствор обрабатывают и перерабатывают способом, аналогичным примеру 1, и полученный продукт перекристаллизовывают из толуола, что дает указанное в заглавии соединение, т.пл. 127-128^oC.

Example 13 [reaction according to method (b)]
Preparation of (R) -N- (1-cyclopropylmethyl-1H-hexaridroazepin-3-yl) - 6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide (compound 13):
Using the appropriate starting compound, an aqueous solution of (R) -5-amino-N- (1-cyclopropylmethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylaminobenzamide is prepared using a reaction and processing method similar to those described below in example 18 and standard examples 1 and 4. This solution is processed and processed in a manner analogous to example 1, and the resulting product is recrystallized from toluene, which gives the specified in the title compound, so pl. 127-128 ^o C.

Example 14 [reaction according to method (a)]
Preparation of N- (1-ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide (compound 14).

Example 6 is repeated, except that 6-methoxy-1H-benzotriazole-5-carboxylic acid and 3-amino-1-ethyl-1H-hexahydroazepine used in example 6 are replaced with 6-methoxy-1-methyl-1H -benzotriazole-5-carboxylic acid and 3-amino-1-ethyl-1H-heptahydroazocin, respectively. The resulting product was recrystallized from ethanol-diethyl ether-mixture, getting mentioned in the title compound, so pl. 116-118 ^o C.

Example 15 [reaction according to method (a)]
Preparation of N- (1-ethyl-1H-octahydroazonin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide (compound 15):
Example 6 is repeated, except that 6-methoxy-1H-benzotriazole-5-carboxylic acid and 3-amino-1-ethyl-1H-hexahydroazepine used in example 6 are replaced with 6-methoxy-1-methyl-1H -benzotriazole-5-carboxylic acid and 3-amino-1-ethyl-1H-octahydroazonine, respectively. The resulting product was recrystallized from ethyl acetate to give the title compound, mp. 155-156 ^o C.

 Examples 16-24 below describe methods for synthesizing intermediates used to prepare the compounds of this invention.

Example 16 [reaction according to method (b)]
Preparation of 1-benzyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide [compound of formula (IIa) in which R ^3a represents a benzyl group]:
To a 6 ml aqueous solution of hydrochloric acid containing about 1.5 g of 5-amino-4-benzylamino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxybenzamide prepared according to standard Example 9, 30 ml of 5N hydrochloric acid and 70 ml of water. Then, 1 ml of an aqueous solution containing 0.29 g of sodium nitrite was added to the solution with cooling, and then stirred for 30 minutes under the same conditions and one hour at room temperature. The reaction mixture was made basic with a 48% aqueous sodium hydroxide solution and extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain an oily residue. The residue was subjected to silica gel column chromatography, eluting and purifying with a mixture of chloroform-methanol (20: 1). The resulting solid was recrystallized from diethyl ether to give 1.1 g of the title compound, mp. 136-137 ^o C.

Example 17 [reaction according to method (a)]
Preparation of 1-Acetyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide [compound of formula (IIb) in which R ^3b represents an acetyl group]:
To 31.5 g of 1-acetyl-6-methoxy-1H-benzotriazole-5-carboxylic acid, 20.3 g of triethylamine and 400 ml of ethyl acetate are added. Then, 17.5 g of ethyl chloroformate was added dropwise to the solution at -7 ^° C to -10 ^° C, followed by stirring for two hours at -5 ^° C to -7 ^° C. Eighty (80 ml) was added dropwise to the mixture. an ethyl acetate solution containing 22.8 g of (R) -3-amino-1-ethyl-1H-hexahydroazepine and stirred for one hour and then for 16 hours at room temperature. The reaction mixture was washed successively with water and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 36 g of the title compound as a solid, mp. 134-135 ^o C (recrystallized from ethyl acetate)
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 1.04 (3H, t, J = 7.0 Hz), 1.5-2.1 (6H, m), 2.45-2, 95 (6H, m), 3.00 (3H, s), 4.09 (3H, s), 4.35 (1H, broad s), 7.76 (1H, s), 8.60 (1H, d, J = 9.0 Hz), 8.95 (1H, s).

Example 18 (reaction according to scheme 1)
Preparation of (R) -3-amino-1-ethyl-1H-hexahydroazepine;
(1) Stage 1:
To a stirred suspension of 173 g of (R) -α-amino-∈-caprolactam hydrochloride, 266 g of triethylamine and 1,700 ml of chloroform, 293 g of chlorotriphenylmethane were added portionwise under ice-cooling. the resulting mixture was stirred for one hour under the same conditions and then two hours at room temperature. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and 600 ml of a mixture of n-hexane-ethyl acetate (2: 1) were added to the resulting oily residue. The resulting crystalline precipitate was collected by filtration, washed with 1,000 ml of a mixture of n-hexane-ethyl acetate (10: 1) and dried, which afforded 290 g of (R) -α-triphenylmethylamino-∈-caprolactam, so pl. 189 ^o C.

(2) Stage 2 ':
To a mixture of 300 g of the product obtained above, 193 g of ethane iodide and 1,500 ml of tetrahydrofuran, 42 g of 60% sodium hydride are gradually added with stirring at room temperature, after which they are stirred for 1.5 hours under the same conditions. The vessel is then cooled with ice water and water is slowly added to the mixture until the insoluble compounds dissolve. The reaction mixture was concentrated under reduced pressure, and 1,000 ml of ethyl acetate was added to the residue. The solution was washed with water, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the resulting oily residue was added 350 ml of a mixture of hexane-ethyl acetate (50: 1) and the resulting crystalline precipitate was collected by filtration and dried, yielding 287 g of (R) -1-ethyl-3-triphenylmethylamino-1H-hexahydroazepin-2-one, t. pl. 127 ^o C.

(3) Stage 3 ':
To 615 g of a 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride, 1400 ml of toluene is added and 280 g of the product obtained above are added to the mixture with stirring and cooling with ice. The solution was stirred for 1.5 hours under the same conditions. Under ice cooling, 1,000 ml of a 15% aqueous sodium hydroxide solution were added to the resulting reaction mixture, and the organic layer was separated, then the aqueous layer was extracted with 1,500 ml of toluene. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The oily residue thus obtained is crystallized from ethanol. The resulting crystals were collected by filtration and dried, yielding 247 g of (R) -1-ethyl-3-triphenylmethylamino-1H-hexahydroazepine, m.p. 83- 84 ^o C.

(4) Stage 4;
To a mixture of 177 g of the above product and 50 ml of tetrahydrofuran was added 700 ml of 10% hydrochloric acid, after which it was stirred at room temperature for 2 hours. The reaction mixture was washed with diethyl ether. Then an excess amount of potassium carbonate is added to the aqueous layer, after which it is extracted with chloroform. The liquid extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Thus, 65 g of the title compound are obtained in the form of an oil.

¹ H-NMR spectrum (CDCl ₃ , δ ppm): 1.04 (3H, t, J = 7.5 Hz), 1.3-1.9 (8H, m), 2.42 (1H, dd, J = 13.5 Hz, 6.9 Hz), 2.5-2.6 (4H, m), 2.70 (1H, dd, J = 13.5, J = 3.5 Hz), 2.98 ( 1H, m).

Example 19 (reaction according to scheme 1)
Preparation of (R) -3-amino-1-cyclopropylmethyl-1H-hexahydroazepine:
(1) Stage 2;
To a mixture of 370 ml of toluene and 37 g of (R) -α-triphenylmethylamino-∈-caprolactam is added dropwise and at room temperature 1,000 ml of a 1M toluene solution of diisobutylaluminohydride, followed by 16 hours of stirring. After termination of the reaction, water was added dropwise to the mixture to decompose the excess diisobutylaluminum hydride. The precipitated salts were removed by filtration, and the filtrate was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Thus, 34 g of (R) -3-triphenylmethylamino-1H-hexahydroazepine are obtained in the form of an oil.

(2) Stage 3:
To a mixture of 10 g of the obtained product and 100 ml of methyl ethyl ketone, 10.5 g of potassium carbonate and 5.1 g of cyclopropylmethyl bromide were added, and the mixture was heated for 5 hours at reflux temperature. After termination of the reaction, insoluble matters were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting and purifying with chloroform-methanol (10: 1), to give 10 g of (R) -1-cyclopropylmethyl-3-triphenylmethylamino-1H-hexahydroazepine as an oil.

(3) Stage 4:
To a mixture of 9.0 g of the product obtained above and 10 ml of tetrahydrofuran, 100 ml of 10% hydrochloric acid was added and subsequently stirred for 5 hours at room temperature. The resulting reaction mixture was washed with diethyl ether and the aqueous layer was saturated with potassium carbonate and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 4.0 g of the title compound as an oil.

Example 20 (reaction according to scheme 1)
Obtaining 3-amino-1-ethyl-1H-hexahydroazepine:
(1) Stage 1:
To a stirred suspension of 125 g of α-amino-∈-caprolactam, 118 g of triethylamine and 600 ml of chloroform, 288 g of chlorotriphenylmethane are added under ice-cooling. The mixture was further stirred for one hour under the same conditions and then stirred for 2 hours at room temperature. The precipitate thus obtained was collected by filtration, washed thoroughly with acetone and dried, yielding 330 g of α-triphenylmethylamino-∈-caprolactam, so pl. 240-241 ^o C.

(2) Stage 2 ':
To a solution of 100 g of the product obtained above and 65 g of ethane iodide in 500 ml of dimethylformamide, 12 g of 60% sodium hydride were gradually added with stirring at room temperature, followed by stirring for 4 hours under the same conditions. Then everything was poured into ice water and extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crystals were collected by filtration and dried, yielding 88 g of 1-ethyl-3-triphenylmethylamino-1H-hexahydroazepin-2-one, mp. 120-121 ^o C.

(3) Stage 3 ':
To 180 g of a 70% toluene solution containing sodium bis (2-methoxyethoxy) aluminum hydride, 800 ml of toluene was added. Then, with stirring and cooling with ice, 83 g of the product obtained above is added, after which it is stirred for one hour under the same conditions and 2 hours at room temperature. While cooling with ice, water and a 48% aqueous sodium hydroxide solution are added to the reaction mixture, and the organic layer is separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The oily residue thus obtained is crystallized from ethanol. The crystals were collected by filtration and dried, yielding 65 g of 1-ethyl-3-triphenylmethylamino-1H-hexahydroazepine, m.p. 85-86 ^o C.

(4) Stage 4:
To a mixture of 134 g of the product obtained above and 30 ml of tetrahydrofuran was added 500 ml of 10% hydrochloric acid, followed by stirring for 2 hours at room temperature. The reaction mixture was washed with diethyl ether. Then excess potassium carbonate is added to the aqueous layer and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 48 g of the title compound as an oil.

¹ H-NMR spectrum (CDCl ₃ , δ ppm): 1.04 (3H, t. J = 7.5 Hz), 1.3-1.9 (8H, m), 2.42 ( 1H, dd J = 13.5 Hz, 6.9 Hz), 2.5-2.6 (4H, m), 2.70 (1H, dd, J = 13.5, J = 3.5 Hz) 2.98 (1H, m).

Example 21 (reaction according to scheme 1)
Obtaining (S) -3-amino-1-ethyl-1H-hexahydroazepine:
Example 20 is repeated, except that the α-amino-∈-caprolactam used in step 1 is replaced here with (S) -α-amino-∈-caprolactam. The title compound was obtained as an oil.

Example 22 (reaction according to scheme 1)
Obtaining 3-amino-1-cyclopropylmethyl-1H-hexahydroazepine:
Example 18 is repeated, except that the (R) -α-triphenylmethylamino-∈-caprolactam used in step 1, in this case, is replaced with α-triphenylmethylamino-∈-caprolactam. The title compound was obtained as an oil.

Example 23 (reaction according to scheme 2)
Obtaining 3-amino-1-ethyl-1H-heptahydroazocin:
(1) Stage 1:
To a solution of 27 g of 2-azacyclooctanone and 50 g of ethane iodide in 250 ml of tetrahydrofuran, 10 g of 60% sodium hydride are gradually added with stirring and ice-cooling. The reaction mixture was stirred for 4 hours at room temperature and poured into ice water, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting and purifying with chloroform-methanol (100: 1), to obtain 36 g of 1-ethyl-1H-heptahydroazocin-2-one as an oil.

¹ H-NMR spectrum (CDCl ₃ , δ ppm): 1.15 (3H, t, J = 7 Hz), 1.4-1.7 (6H, m), 1.82 (2H, m), 2.48 (2H, m), 3.38 (2H, q, J = 7 Hz), 3.47 (2H, m).

(2) Stage 2:
To a solution of 25 g of the product obtained above in 250 ml of chloroform, 34 g of phosphorus pentachloride are added portionwise with stirring and ice-cooling, followed by an additional 30 minutes stirring under the same conditions. To the resulting mixture, 0.4 g of iodine is added with stirring and ice-cooling, and then 25 g of bromine are slowly added dropwise under the same conditions, followed by heating to reflux for 2 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water and an aqueous sodium thiosulfate solution, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

 The residue was subjected to silica gel column chromatography, eluting and purifying with n-hexane-ethyl acetate (4: 1). The crystals thus obtained were recrystallized from n-hexane to obtain 10 g of a mixture of 3-bromo-1-ethyl-1H-heptahydroazocin-2-one and 3-chloro-1-ethyl-1H-heptahydroazocin-2-one.

(3) Stage 3:
A mixture of 10 g of the mixture obtained above, 12 g of sodium azide, 2.0 g of sodium iodide and 100 ml of dimethylformamide was stirred overnight at 80 ^° C., poured into ice water and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, eluting and purifying with n-hexane-ethyl acetate (4: 1), which afforded 4.8 g of 3-azide-1-ethyl-1H-heptahydroazocin-2-one as an oil.

¹ H-NMR spectrum (CDCl ₃ , δ ppm): 1.18 (3H, t, J = 7 Hz), 1.5-1.8 (6H, m), 2.2 (2H, m), 3.08 (1H, m), 3.28 (1H, m), 3.53 (1H, m), 3.76 (1H, m), 4.0 (1H, dd, J = 10 5 Hz, J = 5.6 Hz).

(4) Stage 4:
To 36.4 g of a 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride is added 100 ml of toluene, and an additional 4.8 g of the product obtained above is gradually added to the resulting solution with stirring and cooling with ice, followed by stirring at room temperature for 2 hours. Water and a 48% aqueous sodium hydroxide solution were successively added to the reaction mixture with stirring and ice-cooling, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.8 g of the title compound as an oil.

Example 24 (reaction according to scheme 3)
Obtaining 3-amino-1-ethyl-1H-octahydroazonin:
(1) To a solution of 17 g of 2-azacyclononanone and 29 g of ethane iodide in 200 ml of 1,2-dimethoxyethane, 6.0 g of 60% sodium hydride was gradually added with stirring at room temperature, followed by stirring under these conditions for 4 hours. Then water is added to the mixture, followed by extraction with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to obtain 20 g of 1-ethyl-1H-octahydroazonin-2-one as an oil.

(2) Stage 1:
To 200 ml of a tetrahydrofuran solution containing 20 g of the product obtained above, 78 ml of lithium 2M-diisopropylamide in tetrahydrofuran was added dropwise and with ice cooling, followed by stirring for one hour. The reaction mixture was poured onto dry ice and the resulting mixture was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with chloroform, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 14 g of 3-carboxy-1-ethyl-1H-octahydroazonin-2-one, mp. 109-110 ^o C (recrystallization from diethyl ether-n-hexane).

(3) Stage (2):
To 100 ml of an acetone solution containing 12 g of the product obtained above, 12 ml of water and 7.0 ml of triethylamine are added. To the resulting mixture, 30 ml of an acetone solution containing 8.0 g of ethyl chloroformate was added dropwise and under ice-cooling, followed by 30 minutes of stirring. Then, 30 ml of an aqueous solution containing 6.1 g of sodium azide was added dropwise to the reaction mixture, which was then stirred for 1.5 hours. The reaction mixture was poured into ice water and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, 200 ml of toluene was added to the obtained residue. The solution was stirred while heating to 70 ^° C. until foaming stopped, and then the temperature was raised to 100 ^° C., followed by 2 hours stirring. After termination of the reaction, the solvent was evaporated under reduced pressure. To the resulting residue, 120 ml of 20% hydrochloric acid are added with stirring and ice-cooling, followed by heating to reflux for 1.5 hours. The reaction mixture was washed with ethyl acetate and the aqueous layer was made basic with excess potassium carbonate and extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 8.5 g of 3-amino-1-ethyl-1H-octahydroazonin-2-one as an oil.

(4) Stage 3:
To a solution of 8.5 g of the product obtained above in chloroform was added 7.0 ml of triethylamine, and then 14 g of chlorotriphenylamine were added portionwise under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction mixture was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography, in which it was eluted and purified with ethyl acetate-n-hexane (1:10) to obtain 14 g of 3-triphenylmethylamino-1-ethyl-1H-octahydroazonin-2-one as a solid, mp. 160-162 ^o C (recrystallization from n-hexane-ethyl acetate).

(5) Stage 4:
To 30 g of a 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride is added 100 ml of toluene, to which then 14 g of the product obtained above are added gradually with stirring and ice-cooling. The mixture was stirred overnight at room temperature. After cooling the reaction mixture, a 2N aqueous sodium hydroxide solution was added dropwise to it, and then a 48% sodium hydroxide solution was added. The solution was extracted with ethyl acetate. The extract was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting and purifying with ethyl acetate-n-hexane (1:10), to give 13 g of 3-triphenylmethylamino-1-ethyl-1H-octahydroazonine.

(6) Stage 5:
To a mixture of 13 g of the product obtained above and 3 ml of tetrahydrofuran, 45 ml of 10% hydrochloric acid was added, followed by stirring for 5 hours at room temperature. The reaction mixture was washed with diethyl ether. The aqueous layer was made basic with excess potassium carbonate and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 5.0 g of the title compound as an oil.

Standard example 1 (reaction according to stage 1 of scheme 4)
Preparation of 4-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide
To a suspension of 14.7 g of 4-chloro-2-methoxy-5-nitrobenzoic acid, 300 ml of chloroform and 1 ml of dimethylformamide were added 22.7 g of thionyl chloride and the mixture was heated for one hour to reflux. After termination of the reaction, the solvent was evaporated under reduced pressure and the residue was dissolved in 200 ml of methylene chloride, 12.9 g of triethylamine and 9.0 g of 3-amino-1-ethyl-1H-hexahydroazepine were added to the mixture, followed by stirring at room temperature within 15 minutes The reaction mixture was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography, eluting and purifying with chloroform-methanol (9: 1), to give 9.8 g of the title compound as a solid.

Standard example 2 (reaction according to stage 1 of scheme 4)
Preparation of (R) -4-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide:
Standard Example 1 was repeated, except that (R) -3-amino-1-ethyl-1H-hexahydroazepine was used. The title compound was obtained as a solid.

Standard example 3 (reaction according to stage 1 of scheme 4)
Preparation of (S) -4-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide:
Standard Example 1 was repeated, except that (S) -3-amino-1-ethyl-1H-hexahydroazepine was used. The title compound was obtained as a solid.

Standard example 4 (reaction according to stage 2 and 3 of scheme 4)
Preparation of 5-amino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylaminobenzamide:
(1) Stage 2:
To 100 ml of ethanol containing 4.9 g of 4-chloro-N - (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide, 50 ml of a 30% ethanol methylamine solution was added, followed by heating to reflux temperature for 1.5 hours. The solvent was evaporated under reduced pressure, and water was added to the resulting residue. The crystals were collected by filtration, washed with water and dried to give 3.6 g of N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylamino-5-nitrobenzamide.

(2) Stage 3:
3.3 g of the product obtained above are dissolved in 200 ml of 20% aqueous methanol. 10% palladium carbon was added to the solution, and the mixture was hydrogenated at atmospheric pressure and room temperature. After the theoretical amount of hydrogen is absorbed, palladium-carbon is removed by filtration and the methanol from the filtrate is evaporated under reduced pressure. Thus, an aqueous solution of the title compound is obtained.

Standard example 5 (reaction in stages 2 and 3 of scheme 4)
Preparation of (R) -5-amino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylaminobenzamide:
(2) Stage 2
To 600 ml of an ethanol solution containing 56.8 g of (R) -4-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide, add 300 ml of a 40% aqueous solution methylamine, followed by heating to boiling point under reflux for 2 hours. The solvent was evaporated under reduced pressure, and the resulting crystalline precipitate was collected by filtration. The precipitate was washed with water and dried, yielding 32 g of (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylamino-5-nitrobenzamide.

(2) Stage 3:
To 33.2 g of the product obtained above, 200 ml of methanol, 400 ml of water, 80 ml of acetic acid and 2.0 g of 10% palladium-carbon are added and the mixture is hydrogenated at atmospheric pressure and room temperature. After the theoretical amount of hydrogen is absorbed, palladium-carbon is removed by filtration and the methanol from the filtrate is evaporated under reduced pressure. An aqueous solution of acetic acid containing the title compound is thus obtained.

Standard Examples 6-8 (Reaction of Steps 2 and 3 of Scheme 4)
Obtaining 4-substituted amino-5-amino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxybenzamide or its optical isomers:
Using 4-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) - 2-methoxy-5-nitrobenzamides having the same configuration as the final products and the corresponding amines, the reaction and treatment are carried out according to the method of standard example 5, obtaining aqueous solutions of the compounds listed in table 7.

Стандартный пример 9 (реакция по стадиям 2 и 3 схемы 4)
Получение 5-амино-4-бензиламино-N-(1-этил-1Н- гексагидроазепин- 3-ил)-2-метоксибензамид:
(1) Стадия 2:
К 50 мл этанольного раствора, содержащего 2,0 г 4-хлор-N -(1-этил-1Н-гексагидроазепин-3-ил)-2-метокси-5-нитробензамида добавляют 6,0 г бензиламина и нагревают до температуры кипения с обратным холодильником 22 часа. Растворитель упаривают при пониженном давлении. К остатку добавляют воду и затем экстрагируют хлороформом. Экстракт промывают насыщенным водным раствором хлористого натрия и сушат над безводным сульфатом натрия; растворитель упаривают при пониженном давлении. Остаток подвергают колоночной хроматографии на силикагеле, элюируя и очищая смесью хлороформ-метанол (12:1), что дает 2,4 г 4-бензиламино-N -(1-этил-1Н-гексагидроазепин-3-ил)-2-метокси-5-нитробензамида в виде твердого вещества.

Standard example 9 (reaction in stages 2 and 3 of scheme 4)
Preparation of 5-amino-4-benzylamino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxybenzamide:
(1) Stage 2:
6.0 ml of benzylamine are added to 50 ml of an ethanol solution containing 2.0 g of 4-chloro-N - (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide and heated to boiling point reflux 22 hours. The solvent was evaporated under reduced pressure. Water was added to the residue and then extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate; the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting and purifying with a mixture of chloroform-methanol (12: 1), to give 2.4 g of 4-benzylamino-N - (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy- 5-nitrobenzamide as a solid.

(2) Stage 3:
To 1.6 g of the product obtained above, 6 ml of conc. hydrochloric acid and 3 ml of ethanol. Then, a solution of 2.6 g of tin chloride • dihydrate in 3 ml of ethanol is further added, followed by stirring for 1 hour at 80 ^° C. After the reaction is terminated, ethanol is evaporated under reduced pressure to obtain an aqueous hydrochloric acid solution containing the title compound.

Standard example 10
Preparation of 6-methoxy-1-methyl-1H-benzotriazole-5-carboxylic acid [a compound of formula (III), in which R ^2a is a methyl group]:
1) Repeat standard example 1, with the exception that 3-amino-1-ethyl-1H-hexahydroazepine is replaced by propylamine. Thus, 4-chloro-2-methoxy-5-nitpo-N-propylbenzamide is obtained as a solid.

 (2) 4-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide used in standard example 4 (1), is replaced by the above product, and the interaction and processing carried out in a manner analogous to standard example 4. Thus, 5-amino-2-methoxy-4-methylamino-N- (1-propyl) benzamide was obtained in the form of a solid.

 (3) 5-amino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylaminobenzamide used in example 1 is replaced with the product obtained above. The reaction and treatment are carried out according to the method of Example 1, which affords 6-methoxy-1-methyl-N- (1-propyl) -1H-benzotriazole-5-carboxamide as a solid compound.

 (4) A mixture of 6.9 g of the product obtained above and 100 ml of conc. hydrochloric acid is heated to the boiling temperature under reflux for 5.5 hours. The reaction mixture was cooled and concentrated under reduced pressure. The resulting crystalline precipitate was collected by filtration, washed with water and dried, yielding 3.2 g of the title compound.

Composition Example 1
Preparation of tablets (per 1,000 tablets):
(R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide (compound 2) - 5 g
Lactose - 80 g
Corn Starch - 30 g
Microcrystalline cellulose - 25 g
Hydroxypropyl cellulose - 3 g
Low Viscous Silicon Anhydride - 0.7 g
Magnesium Stearate - 1.3 g
The above components are mixed and granulated in the usual way, 1.000 tablets (145 mg / tablet) are obtained by tabletting.

Composition Example 2
Obtaining capsules (per 1,000 capsules):
(R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide • 3/2 fumarate (compound 7b) - 10 g
Lactose - 160 g
Corn Starch - 22 g
Hydroxypropyl cellulose - 3.5 g
Low Viscosity Silicon Anhydride - 1.8 g
Magnesium Stearate - 2.7 g
The above compounds are mixed, granulated in a conventional manner and filled into 1,000 capsules.

Composition Example 3
Powder production:
(R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide • 3/2 fumarate (compound 7b) - 10 g
Lactose - 960 g
Hydroxypropyl cellulose - 25 g
Low Viscous Silicon Anhydride - 5 g
These components are mixed and formulated into a powdered preparation in a conventional manner.

Example composition 4
The drug for injection (per 1,000 ampoules):
(R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide • 3/2 fumarate (compound 7b) - 10 g
Sorbitol - 100 g
Water for injection - gs - Total 2.000 ml
(R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide • 3/2 fumarate and sorbitol are dissolved in a portion of the water for injection. The remainder of the water for injection is added to the total. The resulting solution was filtered through a membrane filter (0.22 μm). The filtrate was filled in 2 ml ampoules and sterilized at 121 ^° C. for 20 minutes.

Industrial applicability
As previously noted, the compounds of this invention represented by formula (I) and their pharmaceutically acceptable acid addition salts have both excellent antiemetic activity and activity enhancing the contractility of the gastrointestinal tract, while exhibiting less suppressive activity against CNS and, therefore, useful as agents that enhance the contractility of the gastrointestinal tract for the treatment or prevention of various functional disorders of the zling tract associated with various diseases and their therapy. The intermediates of this invention are useful as synthetic intermediates for compounds of formula (I) in which R ² is a hydrogen atom. In addition, the intermediates of this invention represented by formula (IVa) are useful as intermediates for compounds of formula (I) having an R configuration.

Claims (11)

1. Derivatives of 6-methoxy-1H-benzotriazole-5-carboxamide of the general formula I

wherein R ¹ is ethyl or cyclopropylmethyl;
R ² represents a hydrogen atom, methyl or ethyl;
n is 1.2 or 3;
wavy line

means that the configuration of the substituents on the carbon atom bound to the nitrogen atom in the amide group is RS, R or S,
or its pharmaceutically acceptable acid addition salts. 2. The compound of formula I according to claim 1, in which R ¹ denotes ethyl, and R ² denotes a hydrogen atom or methyl group.  3. The compound according to claim 1 or 2, having an R-configuration.  4. The compound according to claim 1 or 2, having an RS configuration.  5. (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide or a pharmaceutically acceptable acid addition salt thereof. 6. A pharmaceutical composition having antiemetic activity and activity enhancing the contractility of the gastrointestinal tract, characterized in that it includes as an active ingredient an effective amount of a 6-methoxy-1H-benzotriazole-5-carboxamide derivative of the general formula I

wherein R ¹ is ethyl or cyclopropylmethyl;
R ² represents a hydrogen atom, methyl or ethyl;
n is 1,2 or 3;
wavy line

means that the configuration of the substituents on the carbon atom bonded to the N atom in the amide group is RS, R or S,
or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.  7. The pharmaceutical composition according to claim 6, characterized in that it comprises as the active ingredient (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide or its pharmaceutically acceptable acid addition salt.  8. The pharmaceutical composition according to claim 6, characterized in that it comprises (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole- as the active ingredient 5-carboxamide or a pharmaceutically acceptable acid addition salt thereof. 9. The method of obtaining 6-methoxy-1H-benzotriazole-5-carboxamide derivative represented by formula I

wherein R ¹ is ethyl or cyclopropylmethyl;
R ² represents a hydrogen atom, methyl or ethyl;
n is 1, 2 or 3;
wavy line

means that the configuration of the substituents on the carbon atom bonded to the nitrogen atom in the amide radical is RS, R or S,
or a pharmaceutically acceptable acid addition salt thereof, comprising reacting a compound represented by formula III

in which R ^2A represents hydrogen, methyl, ethyl or an amino protecting group,
or its reactive derivative with a compound represented by formula IV

wherein R ¹ is ethyl or cyclopropylmethyl;
n is 1, 2 or 3;
wavy line

means that the configuration of the substituents on the carbon atom bound to the N atom of the amide group is RS, R or S,
and when a compound of formula III in which R ^2a is an amino protecting group is used as one of the reactants, R ^2a in the corresponding product is converted to a hydrogen atom by hydrolysis or hydrogenolysis of the product and, if necessary, the resulting product is converted into its pharmaceutically acceptable acid addition salt . 10. Derived 6-methoxy-1H-benzotriazole-5-carboxamide of the formula II

wherein R ¹ is ethyl or cyclopropylmethyl;
R ³ represents an amino protecting group;
n is 1, 2 or 3;
wavy line

means that the configuration of the substituents on the carbon atom bonded to the N atom in the amide radical is RS, R or S,
or its acid addition salt. 11. Derivative of (R) -3-amino-1H-hexahydroazepine of formula IVb

in which R ¹ denotes ethyl or cyclopropylmethyl,
or its acid addition salt.

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